Is FAT2 p.Ala249Val (c.746C>T) pathogenic?

FAT2 p.Ala249Val (c.746C>T) is classified Uncertain significance in FAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-01). AlphaMissense: likely benign (0.0789); Very rare (popmax 0.00695%, nfe).

How common is FAT2 p.Ala249Val (c.746C>T) in the general population?

FAT2 p.Ala249Val (c.746C>T) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about FAT2 p.Ala249Val (c.746C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

FAT2 p.Ala249Val

c.746C>T · VCV3513228

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.2, phastCons 0.98
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	15.02	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00695% European (non-Finnish) · 82/1,179,970 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00558% 90/1,613,898 alleles · very rare exomes 80/1,461,708 · genomes 10/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,390
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.005%	20,002
African / African-American	0.00133%	74,918

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FAT2
Protein: p.Ala249Val
Coding: c.746C>T
MANE Select: NM_001447
Type: single nucleotide variant
Location: chr5:151568186 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 249: the cadherin 2 domain

Full FAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FAT2 p.Ala1009Val Uncertain significance ★★ ⚠ same type
FAT2 p.Ala1078Thr Uncertain significance ★★ ⚠ same type
FAT2 p.Ala1079Asp Uncertain significance ★★ ⚠ same type
FAT2 p.Ala1975Glu Uncertain significance ★★ same type
FAT2 p.Ala2491Glu Uncertain significance ★★ same type
FAT2 p.Ala2587Val Uncertain significance ★★ same type
FAT2 p.Ala2618Thr Uncertain significance ★★ same type
FAT2 p.Ala3055Thr Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fat2-p-ala249val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown